Syphilis, a chronic, complex sexually transmitted disease of humans caused by the spirochetal bacterium Treponema pallidum, remains a global public health problems. Although the immunology of syphilis is complex, clinical manifestations in all stages of syphilis derive principally from cell-mediated processes that are "triggered" by T. pallidum as it invades and replicates with genital skin. The actual cell type than initiates this early immune response thus far has not been identified. Over the past decade,, overwhelming evidence suggests that dendritic cells (DCs) (e.g. Langerhans cells [LCs] of the epidermis and dermal dendritic cells [DDCs] are crucial for the initiation of primary T cell responses to foreign antigens. The working hypothesis for this second-year continuation application is that DCS likely serve as the pivotal immune effector cells that initiate the cellular inflammatory response during syphilis. Thus far, DCs in the cellular immune responses to T. pallidum have not been studied. Accordingly, the Specific Aims of this project have been (1) to characterize the interaction(s) of virulent T. pallidum with DCs, with emphasis on examining phagocytic processes, (2) To assess DC activation and/or maturation following exposure of immature DCs to T. pallidum or its constituent pro-inflammatory membrane lipoproteins, and (3) To examine whether tissue migration is induced following exposure of DCs to T. pallidum or its membrane lipoproteins (longer range goal). Much progress already has been made over the last eight months towards accomplishing Specific Aims 1 and 2, utilizing two immortalized murine DC lines, XS52 and XS 106, developed and provided by Dr. Akira Takashima of the U.T. Southwestern Skin Disease Research Center. In Specific Aim 3; we will employ human skin organ cultures to examine T. pallidum- or lipoprotein-induced DC migration and activation. This study is likely to yield important new insights into the role(s) of DCS as key effector cells in the immunopathogenesis of syphilis.